Induction of WNT inhibitory factor 1 expression by Müllerian inhibiting substance/antiMullerian hormone in the Müllerian duct mesenchyme is linked to Müllerian duct regression

摘要

AkeyeventduringmammaliansexualdevelopmentisregressionoftheMuuml;llerianducts(MDs)inthebipotentialurogenitalridges(UGRs)offetalmales,whichiscausedbytheexpressionofMuuml;llerianinhibitingsubstance(MIS)intheSertolicellsofthedifferentiatingtestes.TheparacrinesignalingmechanismsinvolvedinMDregressionarenotcompletelyunderstood,particularlysincethereceptorforMIS,MISR2,isexpressedinthemesenchymesurroundingtheMD,butregressionoccursinboththeepitheliumandmesenchyme.MicroarrayanalysiscomparingMISsignalingcompetentandemMisr2/emknockoutembryonicUGRswasperformedtoidentifysecretedfactorsthatmightbeimportantforMIS-mediatedregressionoftheMD.Aseven-foldincreaseintheexpressionofemWif1/em,aninhibitorofWNT/β-cateninsignaling,wasobservedintheemMisr2/em-expressingUGRs.WholemountinsituhybridizationofemWif1/emrevealedaspatialandtemporalpatternofexpressionconsistentwithemMisr2/emduringthewindowofMDregressioninthemesenchymesurroundingtheMDepitheliumthatwasabsentinbothfemaleUGRsandUGRsknockedoutforemMisr2/em.KnockdownofemWif1/emexpressioninmaleUGRsbyemWif1/em-specificsiRNAsbeginningonembryonicday13.5resultedinMDretentioninanorgancultureassay,andexposureoffemaleUGRstoaddedrecombinanthumanMISinducedemWif1/emexpressionintheMDmesenchyme.KnockdownofemWif1/emledtoincreasedexpressionofβ-cateninanditsdownstreamtargetsTCF1/LEF1intheMDmesenchymeandtodecreasedapoptosis,resultinginpartialtocompleteretentionoftheMD.TheseresultsstronglysuggestthatWIF1secretionbytheMDmesenchymeplaysaroleinMDregressioninfetalmales./p/div